Obesity is associated with a number of metabolic and cardiovascular disease risk factors including insulin resistance, high blood pressure and dysregulation of lipid and glucose metabolism. Stearoyl-CoA desaturase- 1 (SCD1) is increased in obesity and catalyzes the conversion of saturated fatty acids (16:0 and 18:0) to mono- unsaturated fatty acids (16:1 and 18:1). SCD1 has been shown to increase the synthesis and secretion of triglycerides following a high-saturated fat or high-carbohydrate diet. Global deletion of SCD1 in mice results in an increase in food intake accompanied by elevations in energy expenditure and reductions in serum triglycerides and adiposity. Oleate (18:1) is the primary product of SCD1 and its infusion into the brain has recently been shown to reduce food intake and decrease the production of glucose from the liver. Pharmacologically-induced increases in fatty acid precursors within the brain produce similar reductions in food intake and glucose output. Dietary methionine restriction (MR) has been used as a mimetic of caloric restriction to increase longevity in rodents. A number of studies have shown that dietary MR increases food intake while paradoxically increasing energy expenditure, reducing adiposity and improving insulin sensitivity. Preliminary studies conducted by our laboratory indicate that dietary MR also decreases SCD1 gene expression in the hypothalamus of the brain and liver. Since reductions in hypothalamic SCD1 expression would be expected to decrease intracellular oleate levels, we hypothesize that dietary MR may generate a signal of decreased nutrient abundance which increases food intake and results in a series of unresolved signaling events in peripheral tissues that lead to increased energy expenditure and decreased body-fat. The objective of the proposed studies will be to identify how dietary MR invokes nutrient sensing mechanisms and produces tissue-specific effects on carbohydrate and lipid metabolism. The Specific Aims of the study will be to 1) determine when the increase in energy intake/expenditure occurs relative to when MR alters hypothalamic and peripheral SCD1 expression and 2) determine whether modulation of SCD1 expression by dietary MR is an essential component of the mechanism used by MR to affect energy homeostasis and limit fat deposition. In Aim 1, food consumption and energy expenditure will be measured immediately following the start of the diet to determine how rapidly MR increases food consumption and energy expenditure in mice. In separate cohorts, mice will be euthanized before and after the onset of increased energy intake/expenditure to determine the specific nuclei of the hypothalamus where SCD1 is reduced. In Aim 2, we will overexpress the SCD1 gene in the hypothalamus after starting the diet to determine if this reverses the metabolic and biochemical effects of the diet. The results of these studies will provide a more thorough understanding of the integrated role of the brain and peripheral tissues in the regulation of energy intake and expenditure. PUBLIC HEALTH RELEVANCE: The results of the proposed studies will lead to a more thorough understanding of the integrated responses of the brain and peripheral tissues to the intake of specific nutrients such as amino acids and fats in the diet. These studies will also provide insight into the capacity of nutrients to functionally remodel the storage and production capacity of fat in adipose tissue. These studies have the potential to enhance our understanding of the causes of obesity and could lead to the development of dietary or pharmacological strategies to reduce the progression of weight-gain and the burden of obesity-related diseases in the United States and throughout the world. NOTE: The critiques below were prepared by the reviewers assigned to this application. These commentaries do not necessarily reflect the position of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their critiques if their positions changed during the discussions of the components assigned to them. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the peer reviewers'commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion.